la-419 and Hypertrophy--Left-Ventricular

LA-419, currently being developed by Lacer SA, is a thiol-containing analog of isosorbide mononitrate that is undergoing assessment in clinical trials for the treatment of chronic ischemic cardiovascular disorders. The compound was originally designed to have a reduced tendency toward tolerance sensitivity - a major limitation of established organic nitrate compounds. The rationale behind the drug design was to include an antioxidant moiety in the drug structure to combat the contribution of oxidative stress in tolerance induction. The compound is at an early stage of development, but has already provided some surprising data. First, LA-419 does not appear to require the nitroxy ester moiety for activity and its actions might not be mediated only by nitric oxide release. Second, unlike conventional nitrates, LA-419 is active in platelets, suggesting a potential role as an antithrombotic agent. Third, LA-419 has a profound impact on left ventricular hypertrophy, making the drug a plausible candidate for several additional potential therapeutic opportunities. In addition, LA-419 has demonstrated potential in the treatment of glaucoma and intestinal disorders. At the time of publication, LA-419 was in phase II clinical trials in patients with chronic ischemic cardiovascular disorders.

Topics: Animals; Antioxidants; Cardiovascular Agents; Cardiovascular Diseases; Disease Models, Animal; Drug Tolerance; Fibrinolytic Agents; Humans; Hypertrophy, Left Ventricular; Isosorbide Dinitrate; Myocardial Ischemia; Nitric Oxide Donors; Patents as Topic; Structure-Activity Relationship; Treatment Outcome

Topics: Animals; Blood Pressure; Humans; Hypertrophy, Left Ventricular; Isosorbide Dinitrate; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase Type III; Ventricular Remodeling

Reduced endogenous NO production has been described in cardiovascular disorders as cardiac hypertrophy and heart failure. The therapy with conventional nitrates is limited by their adverse hemodynamic effects and drug tolerance. The novel NO donor LA419 has demonstrated important antithrombotic and anti-ischemic properties without those adverse effects. The aim of this study was to evaluate the effect of LA419 chronic treatment on cardiac hypertrophy development in a progressive model of left ventricular hypertrophy. Rats were randomly divided into 6 groups: sham and clip (euthanized 7 weeks after aortic stenosis), sham+vehicle, sham+LA419, clip+vehicle, and clip+LA419 (euthanized 14 weeks after the surgery and treated with vehicle or 30 mg/kg of LA419 once left ventricular hypertrophy was established). LA419 treatment for 7 weeks induced a marked reduction in the heart:body weight ratio (4.10+/-0.28 and 3.38+/-0.06 mg/g in clip+vehicle versus clip+LA419; P<0.001) and left ventricular diameter (11.96+/-0.25 and 9.90+/-0.20 mm in clip+vehicle versus clip+LA419; P<0.001) without modifying the high blood pressure observed in stenosed rats. Histological analysis revealed that LA419 attenuated myocardial and perivascular fibrosis observed in rats with pressure overload for 14 weeks. In addition, LA419 treatment restored endothelial NO synthase and caveolin-3 expression levels, enhanced the interaction between endothelial NO synthase and its positive regulator the heat shock protein 90, and re-established the normal cardiac content of cGMP in stenosed rats. Thus, LA419 prevented the progression to maladaptative cardiac hypertrophy in response to prolonged pressure overload through a mechanism that involved the re-establishment of the endothelial NO synthase signaling pathway.

Topics: Animals; Blood Pressure; Caveolin 3; Cyclic GMP; Fibrosis; HSP90 Heat-Shock Proteins; Hypertrophy, Left Ventricular; Isosorbide Dinitrate; Male; Myocardium; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase Type III; Rats; Rats, Sprague-Dawley; Ventricular Remodeling